The mammalian olfactory system is increasingly seen as an attractive model system for the study of the formation of neural circuits during development and for plasticity at later stages. Olfactory sensory neurons (OSNs) are believed to express typically one of M 000 odorant receptor (OR) genes. Cell bodies of OSNs expressing a given OR gene are dispersed in one of four zones within the olfactory epithelium, and their axons converge onto a small number of the -1800 glomeruli in the olfactory bulb of the mouse. A phenomenal wiring problem is thus posed: -1000 populations of OSNs, each expressing a distinct OR, must be sorted onto ~1800 glomeruli. The overall aim of our studies continues to be the wiring problem in the mouse olfactory system, which we address through genetic manipulation. The progress report outlines three studies: the identification of odorous ligands for two ORs; evidence that an OR swap results in projection of OSN axons to novel glomeruli; and the characterization of the largest known cluster of OR genes in the mouse genome. Our hypotheses are that the glomerular array of the mammalian olfactory bulb has a substantial degree of plasticity and is influenced by the odorous environment. Aim 1: Does the odorous environment influence the plasticity of the glomerular array? We will expose mice with tagged OR genes to the cognate odorous ligands, and examine the impact of this odor experience on the convergence of axonal projections. Aim 2: How is the glomerular array affected by genomic deletion of 10% of all odorant receptor genes? We will apply the technique of chromosome engineering to excise neatly a 2.4 Mb region of the mouse genome that encompasses a cluster of-100 OR genes, or 10% of the total repertoire. We will examine the molecular and anatomical consequences of this massive gene deletion in the mutant mice. Aim 3: Are the ectopic glomeruli observed in odorant receptor swaps novel and how do they develop? We will determine the level of anatomical homogeneity of the ectopic glomeruli observed when an OR coding sequence is replaced by another one. We will describe how these ectopic glomeruli emerge during development. We will compare the observations to those made in the corresponding endogenous glomeruli. As the brain must be wired properly in order to function properly, the proposed studies will thus be relevant for understanding and treating neurological and psychiatric disorders. [unreadable] [unreadable]